Prostate cancer is a cancer that forms in tissues of the prostate, a gland in the male reproductive system. Prostate cancer usually occurs in older men. More than one million prostate biopsies are performed each year in the United States, leading to over 200,000 prostate cancer diagnoses. Managing the care of these patients is challenging, as the tumors can range from quite indolent to highly aggressive.
Current practice is to stratify patients according to risk based on serum prostate specific antigen (PSA) measurements, TNM staging, and Gleason score. High baseline PSA (PSA>20 ng/ml) is taken as a signal of increased risk of aggressive disease and indicates immediate therapeutic intervention. TNM staging of T3a or worse, including metastatic disease, places the patient in the high risk category, whereas a staging of T1 to T2a is required for the patient to be classified as low or very low risk.
In order to have the Gleason score evaluated, a set of biopsies are taken from different regions of the prostate, using hollow needles. When seen through a microscope, the biopsies may exhibit five different patterns (numbered from 1 to 5), according to the distribution/shape/lack of cells and glands. A pathologist decides what the dominant pattern is (Primary Gleason Score) and the next-most frequent pattern (Secondary Gleason Score). The Primary and Secondary scores are then summed up and a Total Gleason Score (TGS) is obtained, ranging from 2 to 10. As the TGS increases the prognosis worsens. Patients with Gleason score of 8 or higher are classified as high risk and are typically scheduled for immediate treatment, such as radical prostatectomy, radiation therapy and/or systemic androgen therapy. Patients with Gleason score of 7 are placed in an intermediate risk category, while patients with Gleason score of 6 or lower are classified as low or very low risk.
Patients diagnosed with very low, low, and intermediate risk prostate cancer are assigned to watchful waiting, an active surveillance protocol. For these patients, levels of serum PSA are monitored and repeat biopsies maybe ordered every 1-4 years. However, despite low baseline PSA and favorable biopsy results, some patients defined as low risk do experience rapid progression. These patients, especially in the younger age group, would benefit from early intervention. Bill-Axelson, A. et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 364, 1708-17 (2011). Improved identification of prostate cancer patients who in fact have poor prognosis and need to be actively treated is of significant clinical importance.
Investigations into various biomarkers which may help in this indication are ongoing. While measurement of total PSA remains one of the most widely accepted tests for prostate cancer diagnostics, a lot of research is focused on finding additional circulating biomarkers of prognosis of the course of the disease. Several alternative types of PSA measurements, such as percentage of free PSA (% fPSA) and PSA kinetics have been evaluated most extensively. Observed % fPSA seems to be a significant predictor of time to treatment in patients in active surveillance, while PSA velocity and PSA doubling time results are often inconsistent. Trock, B. J. Circulating biomarkers for discriminating indolent from aggressive disease in prostate cancer active surveillance. Curr Opin Urol 24, 293-302 (2014); Cary, K. C. & Cooperberg, M. R. Biomarkers in prostate cancer surveillance and screening: past, present, and future. Ther Adv Urol 5, 318-29 (2013). Another test based on calculating the Prostate Health Index using measurements of [−2]proPSA (a truncated PSA isoform), fPSA and total PSA, has shown promising results. See the Trock paper, supra. Several studies evaluated potential biomarkers in urine, such as prostate cancer antigen3 (PCA3) and fusion gene TMPRSS2-EGR, though the results were contradictory. Id. In addition, there are several recent tissue based tests employing gene expression profiles, such as Oncotype DX Prostate Cancer Assay (Genomic health) see Klein, A. E., et al. A 17-gene Assay to Predict Prostate Cancer Aggressiveness in the Context of Gleason Grade Heterogeneity, Tumor Multifocality, and Biopsy Undersampling, Euro Urol 66, 550-560 (2014) and the Prolaris assay (Myriad Genetics), see Cooperberg, M. R., et al. Validation of a Cell-Cycle Progression Gene Panel to Improve Risk Stratification in a Contemporary Prostatectomy Cohort, J Clin Oncol 31, 1428-1434 (2013), which are associated with the risk of disease progression (see Sartori, D. A. & Chan, D. W. Biomarkers in prostate cancer: what's new? Curr Opin Oncol 26, 259-64 (2014)) however they require an invasive procedure.
Though the results on a number of biomarkers are promising, most are in early stages of validation and none of them has yet been shown to reliably predict the course of the disease. Thus, there is an unmet need for non-invasive clinical tests that would improve risk discrimination of prostate cancer in order to help select appropriate candidates for watchful waiting and identify men who need an immediate active treatment. The methods and systems of this invention meet that need.
Other prior art of interest includes U.S. Pat. Nos. 8,440,409 and 7,811,772, and U.S. patent application publication 2009/0208921. The assignee of the present invention has several patents disclosing classifiers for predictive tests using mass spectrometry data including, among others, U.S. Pat. Nos. 7,736,905; 8,718,996 and 7,906,342.